Abstract 421: TREM-Like Transcript 1 and Hyperlipidemia: A New Pandora's Box
While it is known that high blood cholesterol levels are associated with increased risk and poor outcomes during cardiovascular disease (CVD), all of the mechanisms that regulate cholesterol levels remain unclear. Recent studies on the Triggering Receptor Expressed in Myeloid (TREM) like transcript (TLT)-1 null mice demonstrate changes in cholesterol regulation. TLT-1 was identified as a platelet specific immunoreceptor prompting our studies on TLT-1’s potential involvement in CVD. We crossed our treml1-/- mice on to the apoe-/- background and placed them on high fat diet (HFD). To our surprise, the treml1-/- /apoe-/- (DKO) mice had total cholesterol levels 1.5 fold higher compared to apoE controls. These changes can be seen in treml1-/- mice that are not on the apoE background as well. There are no cholesterol differences in mice not on HFD, demonstrating that these changes are diet-induced. These differences led us to investigate, “why the treml1-/- mouse has higher cholesterol?” Serum chemistry panels reveal high triglycerides, increased glucose levels, and potential liver damage in the treml1-/- mice. Histological evaluation of liver sections revealed large lipid-filled vacuoles and ballooning of DKO and treml1-/- hepatocytes suggesting direct liver involvement in regulating the aforementioned cholesterol levels. What brings these findings together is that we have identified an alternate transcript of TLT-1, TLT-1s, associated with mitochondrial fractions of hepatocytes. Immunohistochemistry of liver sections demonstrate a unique TLT-1s expression in the perivascular hepatocytes of the central vein. Preliminary metabolic analysis of mice livers confirm the hyperlipidemia and demonstrate significant changes in protein metabolism as well as Krebs cycle intermediates. Interestingly, treml1-/- mice have smaller lesions in the aortic sinus which may be explained by less reactive treml1-/- platelets (Gonzalez et al.). Our data suggests that treml1 gene products may affect energy metabolism and mutations in TLT-1 may affect energy use in platelets. This uncanny hypothesis potentially explains how we could have high cholesterol levels, with smaller atherosclerotic lesions and less reactive platelets in the face of hyperlipidemia.
Author Disclosures: M. Gonzalez: None. C. Morán: None. J.J. Vélez: None. C.J. Collado: None. N. Cruz: None. J. Quidley: None. M.J. Crespo: None. N. Chorna: None. A.V. Washington: None.
- © 2014 by American Heart Association, Inc.